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Title: Investigating protein complexes that are involved in the function and regulation of the human INK4a/ARF locus
Author: Nicholls, James Ronald
ISNI:       0000 0001 3445 9109
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2006
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A common mechanism used by cancer cells to over-ride normal restraints on cellular proliferation is abrogation of the tumour suppressive functions of the INK4a/ARF locus. This can be achieved either through genetic changes to the locus or by dysregulation of the molecular pathways that operate to mediate its function or transcriptional regulation. The INK4a/ARF locus encodes two structurally unrelated proteins which have a common exon translated in alternative reading frames. These proteins are named p16INK4a and p14ARF and they both have antiproliferative effects mediated by the Rb and p53 pathways respectively. In this thesis, proteomic approaches have been used to map out some of the protein-protein interaction networks that are involved in function or regulation of INK4a/ARF. Multiprotein complexes are involved both in function (D cyclin-Cdk) and regulation (Cbx7) of the locus and a major focus of this work has been the determination of their molecular composition. The main findings of this thesis relate to the protein-protein interactions of Cbx7, a known transcriptional repressor of INK4A/ARF, which has been implicated as an oncogene. In an analogous manner to other members of the Polycomb group (PcG) of proteins, it was found to participate in a large multiprotein complex. Constituents of a Cbx7 complex isolated from human cells were identified by mass spectrometry. Analysis revealed that it was made up of a subset of the known human PcG proteins and some novel interacting proteins, including an RNA helicase, which had not previously been reported in PcG complexes. The specificity of these interactions was then validated by other biochemical methods. The impact of some of these interactions on the repressive function of Cbx7 has been evaluated in primary human fibroblasts, with a view to understanding how the complex silences transcription.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available